The potential role of endoscopic ultrasound in primary sclerosing cholangitis
Authors: Barbara Lattanzi, Francesco Covotta, Vincenzo Cardinale
Journal: Journal of Hepatology (2023)

Advanced endoscopy meets molecular diagnosis of cholangiocarcinomaJournal of HepatologyVol. 78Issue 5PreviewCholangiocarcinoma remains an aggressive and deadly malignancy that is often diagnosed late. Intrinsic tumour characteristics and the growth pattern of cancer cells contribute to the challenges of diagnosis and chemoresistance. However, establishing an early and accurate diagnosis, and in some instances identifying targetable changes, has the potential to impact survival. Primary sclerosing cholangitis, a chronic cholangiopathy prodromal to the development of a minority of cholangiocarcinomas, poses a particular diagnostic challenge. Full-Text PDF We read with interest the recent manuscript by Cadamuro et al.,1Cadamuro M. Al-Taee A. Gonda T.A. Advanced endoscopy meets molecular diagnosis of cholangiocarcinoma.J Hepatol. 2023 Feb 4; S0168-S8278: 80-86Google Scholar wherein they extensively discuss molecular mechanisms and diagnostic approaches in perihilar/distal cholangiocarcinoma (p/dCCA). Due to the poor prognosis of CCA, an early diagnosis remains the first important aspect of disease management. In the article, endoscopic ultrasound with fine needle tissue acquisition (EUS FNA/FNB) together with endoscopic retrograde cholangiopancreatography (ERCP) is proposed for the diagnosis of sporadic indeterminate biliary strictures, however, in patients affected by primary sclerosing cholangitis (PSC) only ERCP with tissue sampling (brushing and/or biopsy) is discussed in case of relevant or possible dominant strictures. In the setting of the sporadic CCA, the recent Italian clinical guidelines suggest EUS with FNA/FNB as the first approach to obtain a definitive diagnosis of p/dCCA.2Cholangiocarcinoma Working GroupItalian clinical practice guidelines on cholangiocarcinoma - Part I: classification, diagnosis and staging.Dig Liver Dis. 2020 Nov; 52: 1282-1293https://doi.org/10.1016/j.dld.2020.06.045Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Notably, a systematic review and meta-analysis found that EUS was superior to ERCP for the diagnosis of malignancy in biliary strictures, and a prospective comparative study showed a higher sensitivity of EUS-FNA in comparison with ERCP with brushing and/or biopsy in diagnosing malignant strictures.3Moura D.T.H. de Moura E.G.H. Matuguma S.E. Dos Santos M.E. Moura E.T.H. Baracat F.I. et al.EUS-FNA versus ERCP for tissue diagnosis of suspect malignant biliary strictures: a prospective comparative study.Endosc Int Open. 2018 Jun; 6: E769-E777Crossref PubMed Google Scholar Actually, the current guidelines for PSC consider EUS in the diagnostic workup of dCCA4European Association for the Study of the LiverEASL clinical practice guidelines on sclerosing cholangitis.J Hepatol. 2022 Sep; 77: 761-806Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar,5Bowlus C.L. Arrivé L. Bergquist A. Deneau M. Forman L. Ilyas S.I. et al.AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma.Hepatology. 2023 Feb 1; 77: 659-702Crossref PubMed Scopus (64) Google Scholar and suggest avoiding tissue sampling in pCCA in possible liver transplantation (LT) candidates. Data on EUS in CCA arising in patients with PSC are scarce and the main concern is about cancer seeding in patients who are potentially candidates for LT. Concerning this point, some case reports described tumor seeding from EUS-FNA.6Facciorusso A. Crinò S.F. Gkolfakis P. Ramai D. Mangiavillano B. Londoño Castillo J. et al.Needle tract seeding after endoscopic ultrasound tissue acquisition of pancreatic lesions: a systematic review and meta-analysis.Diagnostics (Basel). 2022 Aug 31; 12: 2113Crossref PubMed Scopus (8) Google Scholar However, these studies are retrospective and often consider the EUS approach together with the percutaneous one, which has been demonstrated to carry a greater risk of tumor seeding. It is also to be considered that several novel methods and devices have been introduced that may reduce the risk of seeding by minimizing the number of FNA/FNB passes and improving the simple acquisition technique. Notably, a retrospective study showed that preoperative EUS-FNA does not affect the survival or progression-free survival of patients with CCA,7El Chafic A.H. DeWitt J. Leblanc J.K. I El Hajj I. Cote G. House M.G. et al.Impact of preoperative endoscopic ultrasound-guided fine needle aspiration on postoperative recurrence and survival in cholangiocarcinoma patients.Endoscopy. 2013; 45: 883-889Crossref PubMed Scopus (74) Google Scholar but no prospective study exists regarding this issue. It is important to underline that cancer seeding is relevant mainly in patients with pCCA who are candidates for resection or transplantation because of peritoneal dissemination, while in dCCA, the planned surgery (the Whipple's resection) includes removing part of the duodenum and therefore the risk of seeding is less concerning. EUS is also useful in determining regional lymph-node (LN) involvement, for which it appears to be superior to CT or MRI,8Malikowski T. Levy M.J. Gleeson F.C. Storm A.C. Vargas E.J. Topazian M.D. et al.Endoscopic ultrasound/fine needle aspiration is effective for lymph node staging in patients with cholangiocarcinoma.Hepatology. 2020 Sep; 72: 940-948Crossref PubMed Scopus (40) Google Scholar which is crucial when evaluating resectability and/or the indication for LT. Thus, although there are no identified LN morphologic criteria to accurately predict the presence of nodal involvement, in case of suspected LN metastasis, EUS tissue sampling may be considered. Considering the high accuracy of EUS-FNA/FNB in the diagnosis of malignancy in the workup of the biliary stricture, we think that this tool may also be considered in patients with PSC in selected clinical scenarios, such as in those with suspected dCCA, and those with suspected LN metastasis. In cases of obstructive jaundice where drainage with ERCP is essential, a combined EUS-ERCP session may be considered due to the higher accuracy of this strategy. Another interesting and unexplored field is the morphologic evaluation of the biliary tree by EUS in patients with suspected PSC,9Lutz H.H. Wasmuth H.E. Streetz K. Tacke F. Koch A. Luedde T. et al.Tischendorf Endoscopic ultrasound as an early diagnostic tool for primary sclerosing cholangitis: a prospective pilot study.J.Endoscopy. 2012 Oct; 44: 934-939Crossref PubMed Scopus (27) Google Scholar and the possibility of finding bile duct modifications on ultrasound that may predict tumor appearance. Indeed, it has recently been demonstrated that PSC tissue alterations diffusely involve the wall of the large intra and extrahepatic bile ducts.10Carpino G. Cardinale V. Folseraas T. Overi D. Grzyb K. Costantini D. et al.Neoplastic transformation of the peribiliary stem cell niche in cholangiocarcinoma arisen in primary sclerosing cholangitis.Hepatology. 2019 Feb; 69 (Epub 2019 Jan 4): 622-638https://doi.org/10.1002/hep.30210Crossref PubMed Scopus (46) Google Scholar Carcinogenesis in PSC is a multistep process, and notably is a diffuse process along the intrahepatic large and extrahepatic bile ducts, with tumor appearance anticipated by typical morphological modifications of the duct wall resulting in progressive thickening associated with inflammation and proliferation of peribiliary gland cells (field cancerization).10Carpino G. Cardinale V. Folseraas T. Overi D. Grzyb K. Costantini D. et al.Neoplastic transformation of the peribiliary stem cell niche in cholangiocarcinoma arisen in primary sclerosing cholangitis.Hepatology. 2019 Feb; 69 (Epub 2019 Jan 4): 622-638https://doi.org/10.1002/hep.30210Crossref PubMed Scopus (46) Google Scholar Therefore, EUS could potentially be used to evaluate diffuse changes of bile ducts, primarily the wall of the ducts, defining those patients affected by PSC with characteristics worthy of close follow-up or further intervention. Moreover, EUS findings suggestive of field cancerization can be highly informative to plan the surgical approach to LT in PSC in order to prevent CCA recurrence.4European Association for the Study of the LiverEASL clinical practice guidelines on sclerosing cholangitis.J Hepatol. 2022 Sep; 77: 761-806Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar In conclusion, EUS represents a promising diagnostic tool in patients with PSC and indeterminate distal biliary strictures and those with a suspicion of regional LN involvement. A detailed morphological study of the extrahepatic biliary tract could open up interesting future scenarios for the early diagnosis of PSC and PSC/CCA. Prospective studies analyzing the peritoneal seeding risk and the EUS correlates of PSC and of the field cancerization-associated tissue modifications in PSC are needed to better address the issue of the role of EUS in PSC. Further technological options, such as contrast-enhanced EUS or the application of elastography to evaluate large intra and extrahepatic bile ducts, could be complementary for the longitudinal evaluation of PSC. The authors received no financial support to produce this manuscript. All authors have no proprietary, financial, professional, or other personal interest of any nature or kind in any product, service, and/or company that could be construed as influencing the position presented in, or the review of this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details. All authors contributed to the manuscript editing and had full control over the preparation of the manuscript. All authors have read and agreed to the published version of the manuscript. The authors would like to thank Prof. Guido Carpino for the revision of the manuscript, critical discussion, and support. 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